RT Journal Article
SR Electronic
T1 Angiopoietin 2 displays a vascular endothelial growth factor dependent synergistic effect in hepatocellular carcinoma development in mice
JF Gut
JO Gut
FD BMJ Publishing Group Ltd and British Society of Gastroenterology
SP 1768
OP 1775
DO 10.1136/gut.2005.067900
VO 54
IS 12
A1 H Yoshiji
A1 S Kuriyama
A1 R Noguchi
A1 J Yoshii
A1 Y Ikenaka
A1 K Yanase
A1 T Namisaki
A1 M Kitade
A1 M Uemura
A1 T Masaki
A1 H Fukui
YR 2005
UL http://gut.bmj.com/content/54/12/1768.abstract
AB Background: Orchestration of two major classes of angiogenic factors—namely, vascular endothelial growth factor (VEGF) and angiopoietin 2 (Ang-2)—has been shown to play a pivotal role in tumour angiogenesis, including hepatocellular carcinoma (HCC). However, few studies have focused on the direct interaction of these factors on in vivo tumour development and angiogenesis. Aim: To examine the interaction between both factors in murine HCC. Methods: We examined the combination effect of VEGF and Ang-2 overexpression by means of a combination of a retroviral tetracycline (tet) regulated gene manipulating system in vivo, by providing tet in the drinking water, and a conventional plasmid gene expression system. Results: Neither Ang-2 nor VEGF overexpression induced proliferation of HCC cells in vitro. In vivo, although overexpression of Ang-2 did not increase tumour development, simultaneous expression of Ang-2 and VEGF synergistically augmented tumour growth and angiogenesis in murine HCC. Ang-2 plus VEGF induced tumour development was markedly attenuated by treatment with neutralising monoclonal antibodies against VEGF receptors. Ang-2 plus VEGF overexpression significantly increased the activities of matrix metalloproteinase (MMP)-2 and MMP-9 in the tumour. Suppression of intratumoral VEGF almost completely abolished this augmentation of MMPs. Conclusions: These results suggest that Ang-2 synergistically augments VEGF mediated HCC development and angiogenesis. This proangiogenic activity was exerted only in the presence of VEGF, at least partly mediated via induction of MMP-2 and MMP-9 in the tumour.